tbuckley/cabot-search huggingface dataset:
Accuracy, acceptability, and feasibility of diagnostic tests for the screening of Strongyloides stercoralis in the field (ESTRELLA): a cross-sectional study in Ecuador
Authors: Francesca Tamarozzi, Ángel G Guevara, Mariella Anselmi, Yosselin Vicuña, Rosanna Prandi, Monica Marquez, Sandra Vivero, Francisco Robinzón Huerlo, Marcia Racines, Cristina Mazzi, Matthew Denwood, Dora Buonfrate
Journal: The Lancet Global Health (2023)

WHO recommends the implementation of control programmes for strongyloidiasis, a neglected tropical disease caused by Strongyloides stercoralis. Specific recommendations on the diagnostic test or tests to be used for such programmes have yet to be defined. The primary objective of this study was to estimate the accuracy of five tests for strongyloidiasis. Secondary objectives were to evaluate acceptability and feasibility of use in an endemic area.The ESTRELLA study was a cross-sectional study for which we enrolled school-age children living in remote villages of Ecuador. Recruitment took place in two periods (Sept 9-19, 2021, and April 18-June 11, 2022). Children supplied one fresh stool sample and underwent blood collection via finger prick. Faecal tests were a modified Baermann method and an in-house real-time PCR test. Antibody assays were a recombinant antigen rapid diagnostic test; a crude antigen-based ELISA (Bordier ELISA); and an ELISA based on two recombinant antigens (Strongy Detect ELISA). A Bayesian latent class model was used to analyse the data.778 children were enrolled in the study and provided the required samples. Strongy Detect ELISA had the highest sensitivity at 83·5% (95% credible interval 73·8-91·8), while Bordier ELISA had the highest specificity (100%, 99·8-100). Bordier ELISA plus either PCR or Baermann had the best performance in terms of positive and negative predictive values. The procedures were well accepted by the target population. However, study staff found the Baermann method cumbersome and time-consuming and were concerned about the amount of plastic waste produced.The combination of Bordier ELISA with either faecal test performed best in this study. Practical aspects (including costs, logistics, and local expertise) should, however, also be taken into consideration when selecting tests in different contexts. Acceptability might differ in other settings.Italian Ministry of Health.For the Spanish translation of the abstract see Supplementary Materials section.
Incidence and prognosis of superficial vein thrombosis during pregnancy and the post-partum period: a Danish nationwide cohort study
Authors: Hanke M G Wiegers, Dóra Körmendiné Farkas, Erzsébet Horváth-Puhó, Saskia Middeldorp, Nick van Es, Henrik T Sørensen
Journal: The Lancet Haematology (2023)
When I use a word . . . .Diagnosing definitions
Authors: Jeffrey K Aronson
Journal: BMJ (2023)

Definitions come in different varieties, as it were diagnostic categories. Here I describe seven types: nominal definitions, which are of two types, word–for–word definitions and word–for–thing definitions; descriptive definitions; stipulative definitions, which can be either intensional or extensional; operational definitions; and ostensive definitions. In each case I give examples from medical practice.
40 years of actigraphy in sleep medicine and current state of the art algorithms
Authors: Matthew R. Patterson, Adonay A. S. Nunes, Dawid Gerstel, Rakesh Pilkar, Tyler Guthrie, Ali Neishabouri, Christine C. Guo
Journal: npj Digital Medicine (2023)

Abstract For the last 40 years, actigraphy or wearable accelerometry has provided an objective, low-burden and ecologically valid approach to assess real-world sleep and circadian patterns, contributing valuable data to epidemiological and clinical insights on sleep and sleep disorders. The proper use of wearable technology in sleep research requires validated algorithms that can derive sleep outcomes from the sensor data. Since the publication of the first automated scoring algorithm by Webster in 1982, a variety of sleep algorithms have been developed and contributed to sleep research, including many recent ones that leverage machine learning and / or deep learning approaches. However, it remains unclear how these algorithms compare to each other on the same data set and if these modern data science approaches improve the analytical validity of sleep outcomes based on wrist-worn acceleration data. This work provides a systematic evaluation across 8 state-of-the-art sleep algorithms on a common sleep data set with polysomnography (PSG) as ground truth. Despite the inclusion of recently published complex algorithms, simple regression-based and heuristic algorithms demonstrated slightly superior performance in sleep-wake classification and sleep outcome estimation. The performance of complex machine learning and deep learning models seem to suffer from poor generalization. This independent and systematic analytical validation of sleep algorithms provides key evidence on the use of wearable digital health technologies for sleep research and care.
DNA repair mechanisms that promote insertion-deletion events during immunoglobulin gene diversification
Authors: Qian Hao, Chuanzong Zhan, Chaoyang Lian, Simin Luo, Wenyi Cao, Binbin Wang, Xia Xie, Xiaofei Ye, Tuantuan Gui, Claudia Voena, Chiara Pighi, Yanyan Wang, Ying Tian, Xin Wang, Pengfei Dai, Yanni Cai, Xiaojing Liu, Shengqun Ouyang, Shiqi Sun, Qianwen Hu, Jun Liu, Youqiong Ye, Jingkun Zhao, Aiguo Lu, Ji-Yang Wang, Chuanxin Huang, Bing Su, Fei-Long Meng, Roberto Chiarle, Qiang Pan-Hammarström, Leng-Siew Yeap
Journal: Science Immunology (2023)

Insertions and deletions (indels) are low-frequency deleterious genomic DNA alterations. Despite their rarity, indels are common, and insertions leading to long complementarity-determining region 3 (CDR3) are vital for antigen-binding functions in broadly neutralizing and polyreactive antibodies targeting viruses. Because of challenges in detecting indels, the mechanism that generates indels during immunoglobulin diversification processes remains poorly understood. We carried out ultra-deep profiling of indels and systematically dissected the underlying mechanisms using passenger-immunoglobulin mouse models. We found that activation-induced cytidine deaminase-dependent ±1-base pair (bp) indels are the most prevalent indel events, biasing deleterious outcomes, whereas longer in-frame indels, especially insertions that can extend the CDR3 length, are rare outcomes. The ±1-bp indels are channeled by base excision repair, but longer indels require additional DNA-processing factors. Ectopic expression of a DNA exonuclease or perturbation of the balance of DNA polymerases can increase the frequency of longer indels, thus paving the way for models that can generate antibodies with long CDR3. Our study reveals the mechanisms that generate beneficial and deleterious indels during the process of antibody somatic hypermutation and has implications in understanding the detrimental genomic alterations in various conditions, including tumorigenesis.
Reply to: Hypothetical model ignores many important pathophysiologic mechanisms in fibromyalgia
Authors: Ana Margarida Pinto, Rinie Geenen, Tor D. Wager, Winfried Häuser, Eva Kosek, Jacob N. Ablin, Kirstine Amris, Jaime Branco, Dan Buskila, João Castelhano, Miguel Castelo-Branco, Leslie J. Crofford, Mary-Ann Fitzcharles, Marina López-Solà, Mariana Luís, Tiago Reis Marques, Philip J. Mease, Filipe Palavra, Jamie L. Rhudy, Lucina Q. Uddin, Paula Castilho, Johannes W. G. Jacobs, José A. P. da Silva
Journal: Nature Reviews Rheumatology (2023)
Hypothetical model ignores many important pathophysiologic mechanisms in fibromyalgia
Authors: Daniel J. Clauw, Ernest H. S. Choy, Vitaly Napadow, Anushka Soni, Kevin F. Boehnke, Bruce Naliboff, Afton L. Hassett, Anne Arewasikporn, Andrew Schrepf, Chelsea M. Kaplan, David Williams, Neil Basu, Rachel S. Bergmans, Richard E. Harris, Steven E. Harte, Andrea Chadwick, Gary J. Macfarlane
Journal: Nature Reviews Rheumatology (2023)
The transcription factor Mef2d regulates B:T synapse–dependent GC-T <sub>FH</sub> differentiation and IL-21–mediated humoral immunity
Authors: Ye-Ji Kim, Jeein Oh, Soohan Jung, Chan Johng Kim, Jinyong Choi, Yoon Kyung Jeon, Hyun Jik Kim, Ji-Won Kim, Chang-Hee Suh, Yoontae Lee, Sin-Hyeog Im, Shane Crotty, Youn Soo Choi
Journal: Science Immunology (2023)

Communication between CD4 T cells and cognate B cells is key for the former to fully mature into germinal center-T follicular helper (GC-TFH) cells and for the latter to mount a CD4 T cell-dependent humoral immune response. Although this interaction occurs in a B:T synapse-dependent manner, how CD4 T cells transcriptionally regulate B:T synapse formation remains largely unknown. Here, we report that Mef2d, an isoform of the myocyte enhancer factor 2 (Mef2) transcription factor family, is a critical regulator of this process. In CD4 T cells, Mef2d negatively regulates expression of Sh2d1a, which encodes SLAM-associated protein (SAP), a critical regulator of B:T synapses. We found that Mef2d regulates Sh2d1a expression via DNA binding-dependent transcriptional repression, inhibiting SAP-dependent B:T synapse formation and preventing antigen-specific CD4 T cells from differentiating into GC-TFH cells. Mef2d also impeded IL-21 production by CD4 T cells, an important B cell help signaling molecule, via direct repression of the Il21 gene. In contrast, CD4 T cell-specific disruption of Mef2d led to a substantial increase in GC-TFH differentiation in response to protein immunization, concurrent with enhanced SAP expression. MEF2D mRNA expression inversely correlates with human systemic lupus erythematosus (SLE) patient autoimmune parameters, including circulating TFH-like cell frequencies, autoantibodies, and SLEDAI scores. These findings highlight Mef2d as a pivotal rheostat in CD4 T cells for controlling GC formation and antibody production by B cells.
Who Modifies the Modifiers: A High-Resolution View of the Genetic Modifiers of Cystic Fibrosis
Authors: Sean Kalra, Michael H. Cho
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Who Modifies the Modifiers: A High Resolution View of the Genetic Modifiers of Cystic Fibrosis." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp. –
European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2023 Update
Authors: Morgan Rouprêt, Thomas Seisen, Alison J. Birtle, Otakar Capoun, Eva M. Compérat, José L. Dominguez-Escrig, Irene Gürses Andersson, Fredrik Liedberg, Paramananthan Mariappan, A. Hugh Mostafid, Benjamin Pradere, Bas W.G. van Rhijn, Shahrokh F. Shariat, Bhavan P. Rai, Francesco Soria, Viktor Soukup, Robbert G. Wood, Evanguelos N. Xylinas, Alexandra Masson-Lecomte, Paolo Gontero
Journal: European Urology (2023)
Seizing opportunities to end TB: a call for ambition and optimism on World TB Day
Authors: Michael Reid, Gavin Yamey, Eric Goosby, Dean Jamison, Marco Schäferhoff
Journal: The Lancet (2023)

March 24 marks World Tuberculosis (TB) Day. It is important to reflect on the progress we have made in the fight against TB and the opportunities that lie ahead. Over the past few years, breakthroughs in research and development mean that treatment of drug-resistant TB has been shortened from 20 months to 6 months,1 and a pipeline of new treatment options means that some forms of drug-susceptible TB might be treatable with as little as 2 months of therapy.2 Additionally, affordable and accurate molecular diagnostics promise to revolutionise how we detect TB.
Three double-dose reinforced hepatitis B revaccination scheme for patients with cirrhosis unresponsive to the standard regimen: an open-label randomised clinical trial
Authors: Álvaro Giráldez-Gallego, Elisa del Pilar Rodríguez-Seguel, Raquel Valencia-Martín, Áurea Morillo-García, Celia Salamanca-Rivera, Ricardo Ruiz-Pérez, María Cuaresma-Duque, Clara Rosso-Fernández, María Teresa Ferrer-Ríos, José Manuel Sousa-Martín, Juan Manuel Praena-Fernández, Trinidad Desongles-Corrales, Aitana Rodríguez-Pérez, Francisco Camino-Durán, Antonia Gasch-Illescas, Javier Ampuero-Herrojo, Juan Manuel Pascasio-Acevedo
Journal: Gut (2023)

Objective We aimed to compare the response rates between two different hepatitis B virus vaccination schedules for cirrhotic subjects who were non-responders to the first three 40 µg doses (month 0-1-2), and identify factors associated with the final response. Design A total of 120 cirrhotic patients (72.5% decompensated) were randomised at a 1:1 ratio to receive a single 40 µg booster vaccination at month 6 (classical arm) versus an additional round of three new 40 µg doses administered at monthly intervals (experimental arm). The main outcome was the rate of postvaccinal anti-hepatitis B surface antibodies levels ≥10 mIU/mL. Results Efficacy by ITT analysis was higher in the experimental arm (46.7%) than in the classical one (25%); OR 2.63, p=0.013. The experimental arm increased response rates compared with the classical one from 31% to 68% (OR 4.72; p=0.007), from 24.4% to 50% (OR 3.09; p=0.012) and from 24.4% to 53.8% (OR 3.62; p=0.007), in Child A, Model for End-Stage Liver Disease (MELD) &lt;15 and MELD-Na&lt;15 patients, respectively. Patients with more advanced liver disease did not benefit from the reinforced scheme. Both regimens showed similar safety profiles. Multivariable analysis showed that the experimental treatment was independently response associated when adjusted across three logistic regression models indicating equivalent cirrhosis severity. Conclusion For cirrhotic patients, the revaccination of non-responders to the first three dose cycle, with three additional 40 µg doses, achieved significantly better response rates to those obtained with an isolated 40 µg booster dose. Trial registration number NCT01884415 .
Comparative effectiveness of different types of exercise in reducing arterial stiffness in children and adolescents: a systematic review and network meta-analysis
Authors: Irene Sequi-Dominguez, Dimitris Mavridis, Iván Cavero-Redondo, Alicia Saz-Lara, Vicente Martinez-Vizcaino, Sergio Núñez de Arenas-Arroyo
Journal: British Journal of Sports Medicine (2023)

Objective Arterial stiffness is an early and detectable marker of vascular changes leading to atherosclerotic cardiovascular disease (ACVD). Our objective was to compare the effectiveness of different types of exercise in reducing arterial stiffness in children and adolescents. Design A systematic review and network meta-analysis (NMA) was conducted including experimental studies reporting the effects of exercise interventions on pulse wave velocity (PWV) in children and adolescents. Data sources Cochrane Central Register of Controlled Trials, EMBASE (via Scopus), PubMed (via Medline) and Web of Science from database inception to 25 March 2022. Eligibility criteria Experimental studies reporting the effects of exercise interventions on PWV in children and adolescents. Results Fourteen studies were included in the NMA, all of them were randomised controlled trials except one quasi-experimental study, with an overall risk of bias of some concern. Regarding PWV reduction, all exercise modalities were more effective than control, with standardised mean difference ranging from −1.93 (95% CI: −2.84 to –1.02) and −1.11 (95% CI: −2.01 to –0.21) for aerobic exercise and high intensity interval training (HIIT), respectively, to −0.59 (95% CI: −1.39 to 0.22) for combined exercise. Only sensorimotor training was not superior to the control group 0.11 (95% CI: −1.10 to 1.32). Conclusion Our results support that exercise interventions, especially aerobic exercise or HIIT, can improve arterial stiffness at early ages. The potential to address ACVD early and mitigate long-term consequences via exercise interventions in children and adolescents with higher arterial stiffness requires further investigation. PROSPERO registration number CRD42022322536.
Neurosyphilis among people with and without HIV infection: A Danish nationwide prospective, population-based cohort study 2015–2021
Authors: Christina Carolina Steenberg Schnohr, Fie Welling Paulsen, Lykke Larsen, Merete Storgaard, Micha Phill Grønholm Jepsen, Hans Rudolf Lüttichau, Lothar Wiese, Birgitte Rønde Hansen, Jacob Bodilsen, Henrik Nielsen, Anne-Mette Lebech, Lars Haukali Omland
Journal: Journal of Infection (2023)

Comparative data on clinical presentation, laboratory characteristics, treatment, and outcome of neurosyphilis (NS) in people living with HIV (PLWH) and NS patients without HIV are scarce.Nationwide, population-based, prospective cohort study on all adults with NS diagnosed between 2015 and 2021 at departments of infectious diseases in Denmark.We identified 108 patients with NS, which equals a yearly incidence of 0.3/100,000 adults. The median age was 49 years, 85 (79%) were male, 43 (40%) were men having sex with men and 20 (22%) were PLWH. Ninety-five (88%) had early NS, 37 (34%) had ocular or ocular and otogenic NS, and 27 (25%) had symptomatic meningitis. Most common symptoms were visual disturbance (44%), skin rash (40%), fatigue (26%) and chancre (17%). Median CSF leukocyte count was 27 × 106 cells/L. PLWH less often had neurological deficits (p = 0.02). Unfavorable outcome was observed in 23 (21%) at discharge of whom 0 were PLWH (p = 0.01). Among the 88 NS patients without HIV a CSF leukocyte count of ≥ 30 × 106 cells/L was associated with unfavorable outcome (OR = 3.3 (95% confidence interval: 1.1-10.4)).PLWH with NS have better outcomes than NS patients without HIV infection.
Inhibiting degradation of 2-arachidonoylglycerol as a therapeutic strategy for neurodegenerative diseases
Authors: Chu Chen
Journal: Pharmacology & Therapeutics (2023)

Endocannabinoids are endogenous lipid signaling mediators that participate in a variety of physiological and pathological processes. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid and is a full agonist of G-protein-coupled cannabinoid receptors (CB1R and CB2R), which are targets of Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive ingredient in cannabis. While 2-AG has been well recognized as a retrograde messenger modulating synaptic transmission and plasticity at both inhibitory GABAergic and excitatory glutamatergic synapses in the brain, growing evidence suggests that 2-AG also functions as an endogenous terminator of neuroinflammation in response to harmful insults, thus maintaining brain homeostasis. Monoacylglycerol lipase (MAGL) is the key enzyme that degrades 2-AG in the brain. The immediate metabolite of 2-AG is arachidonic acid (AA), a precursor of prostaglandins (PGs) and leukotrienes. Several lines of evidence indicate that pharmacological or genetic inactivation of MAGL, which boosts 2-AG levels and reduces its hydrolytic metabolites, resolves neuroinflammation, mitigates neuropathology, and improves synaptic and cognitive functions in animal models of neurodegenerative diseases, including Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), and traumatic brain injury (TBI)-induced neurodegenerative disease. Thus, it has been proposed that MAGL is a potential therapeutic target for treatment of neurodegenerative diseases. As the main enzyme hydrolyzing 2-AG, several MAGL inhibitors have been identified and developed. However, our understanding of the mechanisms by which inactivation of MAGL produces neuroprotective effects in neurodegenerative diseases remains limited. A recent finding that inhibition of 2-AG metabolism in astrocytes, but not in neurons, protects the brain from TBI-induced neuropathology might shed some light on this unsolved issue. This review provides an overview of MAGL as a potential therapeutic target for neurodegenerative diseases and discusses possible mechanisms underlying the neuroprotective effects of restraining degradation of 2-AG in the brain.
Omalizumab ameliorates extrarespiratory symptoms in patients with aspirin-exacerbated respiratory disease
Authors: Hiroaki Hayashi, Yuma Fukutomi, Chihiro Mitsui, Keiichi Kajiwara, Kentaro Watai, Yasuhiro Tomita, Yosuke Kamide, Takahiro Tsuburai, Kiyoshi Sekiya, Makoto Ishii, Yoshinori Hasegawa, Masami Taniguchi
Journal: Journal of Allergy and Clinical Immunology (2023)
Evaluation of repRNA vaccine for induction and in utero transfer of maternal antibodies in a pregnant rabbit model
Authors: Amit P. Khandhar, Chelsea D. Landon, Jacob Archer, Kyle Krieger, Nikole L. Warner, Samantha Randall, Bryan J. Berube, Jesse H. Erasmus, D. Noah Sather, Herman F. Staats
Journal: Molecular Therapy (2023)

Mother-to-child transmission is a major route for infections in newborns. Vaccination in mothers to leverage the maternal immune system is a promising approach to vertically transfer protective immunity. During infectious disease outbreaks, such as the 2016 Zika virus (ZIKV) outbreak, rapid availability of vaccines can prove critical in reducing widespread disease burden. The recent successes of mRNA vaccines support their evaluation in pregnant animal models to justify their use in neonatal settings. Here we evaluated immunogenicity of self-amplifying replicon (repRNA) vaccines, delivered with our clinical-stage LION nanoparticle formulation, in pregnant rabbits using ZIKV and HIV-1 as model disease targets. We showed that LION/repRNA vaccines induced robust antigen-specific antibody responses in adult pregnant rabbits that passively transferred to newborn kits in utero. Using a matrixed study design, we further elucidate the effect of vaccination in kits on the presence of pre-existing maternal antibodies. Our findings showed that timing of maternal vaccination is critical in maximizing in utero antibody transfer, and subsequent vaccination in newborns maintained elevated antibody levels compared with no vaccination. Overall, our results support further development of the LION/repRNA vaccine platform for maternal and neonatal settings. Mother-to-child transmission is a major route for infections in newborns. Vaccination in mothers to leverage the maternal immune system is a promising approach to vertically transfer protective immunity. During infectious disease outbreaks, such as the 2016 Zika virus (ZIKV) outbreak, rapid availability of vaccines can prove critical in reducing widespread disease burden. The recent successes of mRNA vaccines support their evaluation in pregnant animal models to justify their use in neonatal settings. Here we evaluated immunogenicity of self-amplifying replicon (repRNA) vaccines, delivered with our clinical-stage LION nanoparticle formulation, in pregnant rabbits using ZIKV and HIV-1 as model disease targets. We showed that LION/repRNA vaccines induced robust antigen-specific antibody responses in adult pregnant rabbits that passively transferred to newborn kits in utero. Using a matrixed study design, we further elucidate the effect of vaccination in kits on the presence of pre-existing maternal antibodies. Our findings showed that timing of maternal vaccination is critical in maximizing in utero antibody transfer, and subsequent vaccination in newborns maintained elevated antibody levels compared with no vaccination. Overall, our results support further development of the LION/repRNA vaccine platform for maternal and neonatal settings.
A synaptic amplifier of hunger for regaining body weight in the hypothalamus
Authors: Katarzyna Grzelka, Hannah Wilhelms, Stephan Dodt, Marie-Luise Dreisow, Joseph C. Madara, Samuel J. Walker, Chen Wu, Daqing Wang, Bradford B. Lowell, Henning Fenselau
Journal: Cell Metabolism (2023)

Restricting caloric intake effectively reduces body weight, but most dieters fail long-term adherence to caloric deficit and eventually regain lost weight. Hypothalamic circuits that control hunger drive critically determine body weight; yet, how weight loss sculpts these circuits to motivate food consumption until lost weight is regained remains unclear. Here, we probe the contribution of synaptic plasticity in discrete excitatory afferents on hunger-promoting AgRP neurons. We reveal a crucial role for activity-dependent, remarkably long-lasting amplification of synaptic activity originating from paraventricular hypothalamus thyrotropin-releasing (PVH